Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

• the present invention provides a method for preparation polymeric micelles and use thereof in pharmaceutical applications.
• the micelle which is used as a carrier for hydrophobic drugs, is prepared via phase separation of a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium.
• Non-ionic surfactants e.g. polyoxyethylene sorbitan fatty acid esters(Tween®) and polyoxyethylene alkyl ethers(BrijTM or MyrjTM)
• Tween® polyoxyethylene sorbitan fatty acid esters
• BrijTM or MyrjTM polyoxyethylene alkyl ethers
• European Patent EP 0645145 discloses a method of solubilizing a typical poorly water soluble drug, paclitaxel, by use of Cremophor ELTM, a polyoxyethylene castor oil derivative.
• Cremophor ELTM a polyoxyethylene castor oil derivative
• Polymeric micelles have been recently investigated as potential carriers for hydrophobic drugs. Eur. J. Pharm. Biopharm. 48(1999) 101-111. Polymeric micelles are characterized by a core-shell structure consisting of hydrophobic inner core and hydrophilic outer shell. A poorly water soluble drug is entrapped within the hydrophobic core of the micelle.
• a block copolymer and a poorly water soluble drug are dissolved in a water-miscible organic solvent, such as ethanol or N,N-dimethyl formamide(DMF), and the solution is dialyzed in water (Dialysis Method); and b) a drug solution of a water-immiscible organic solvent, such as dichloromethane or chloroform, is added to an aqueous polymeric solution and the organic solvent is evaporated from the solution mixture (O/W Emulsion-Solvent Evaporation Method).
• a water-miscible organic solvent such as ethanol or N,N-dimethyl formamide(DMF)
• Yokoyama et al. discloses methods of incorporating a poorly water soluble drug into the inner core of a polymeric micelle using an A-B type diblock copolymer composed of a hydrophilic methoxypolyethylene glycol block(A) and a hydrophobic polyamino acid(B). See U.S. Pat. Nos. 5,510,103 and 5,449,513. According to those patents, an aqueous micellar solution of the diblock copolymer and an organic solvent solution of the hydrophobic component are prepared in separate containers. The two solutions are then mixed and simply stirred, heated or sonicated to incorporate the hydrophobic drug into the polymeric micelles.
• aqueous polymer solution and the drug solution in DMF are mixed together and the mixture is dialyzed against an excess of water.
• These methods require preparing an aqueous micellar solution prior to incorporating a drug into the polymeric micelle. See also, G. Kwon, et al., Block copolymer micelles for drug delivery: loading and release of doxorubicin, J. Contr. Rel. 48(1997) 195 ⁇ 201; G. Kwon, et al., Physical entrapment of Adriamycin in AB block copolymer micelles, Pharm. Res. 12(1995) 192 ⁇ 195.
• X. Zhang et al. reported that a polymeric micelle prepared with a diblock copolymer of poly(lactic acid) and monomethoxy poly(ethylene glycol) was useful as a carrier of paclitaxel.
• X. Zhang et al. Int. J. Pharm. 132(1996) 195-206.
• Shin et al. disclose a solubilization method for indomethacin using a diblock copolymer of poly(ethylene glycol) and polycaprolactone. I. Gyun Shin et al., J. Contr. Rel., 51(1998) 13-22. In these methods, a poorly water soluble drug is incorporated in a polymeric micelle wherein the polymers are biocompatible and biodegradable.
• a drug and a block copolymer are dissolved together in an organic solvent, especially in a water-miscible organic solvent, such as tetrahydrofuran or dimethyl formamide.
• the polymeric micelles are prepared by first dialyzing the solution in water and then freeze-drying the aqueous micellar solution.
• a solution of a polymer and drug in a water-miscible organic solvent, acetonitrile is prepared.
• the organic solvent is slowly evaporated to give a homogeneous drug-polymer matrix and the matrix is then dispersed in an aqueous medium at about 60° C. to form the polymeric micelles.
• a polymeric micelle containing the drug cannot be formed if an organic solvent other than an acetonitrile, such as chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, or tetrahydrofuran is used for dissolving the drug and polymer.
• an organic solvent other than an acetonitrile such as chloroform, dichloromethane, ethyl acetate, acetone, methanol, ethanol, or tetrahydrofuran is used for dissolving the drug and polymer.
• the aqueous polymeric micellar solutions are prepared by heating, ultrasonic treatment, vortexing or mechanical mixing.
• the present invention discloses a preparation method for preparation of a non-aqueous polymeric micellar system without the use of significant amounts of an organic solvent which may have toxic side effects and require removal by evaporation.
• the present invention provides a method for preparing a polymeric micellar composition wherein a hydrophobic drug is effectively incorporated, via phase separation of a biodegradable polymeric composition containing a block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component suspended in a poly(ethylene glycol) medium, into the micelle.
• the block copolymer is mixed together with a hydrophobic drug in the liquid polyethylene glycol.
• a solution of the polymer and the drug is then obtained by heating the mixture.
• the solution is then slowly cooled and polymeric micelles having a core-shell structure form in the solution via phase separation of the block copolymer from the liquid poly(ethylene glycol).
• poly(ethylene glycol), polyethylene glycol, or PEG, as used herein, are interchangeable and shall also be deemed to include derivatives of PEG unless otherwise specifically stated. Such derivatives will be more specifically described in the disclosure that follows.
• the block copolymer forms a core-shell structure wherein the hydrophobic biodegradable polymer block occupies the inner core and the hydrophilic poly(alkylene glycol) block forms the outer shell in the poly(ethylene glycol) medium or carrier.
• the present invention uses liquid polyethylene glycol as a medium for mixing and solubilization of a hydrophobic drug and the hydrophilic/hydrophobic copolymer, followed by phase separation of the polymeric micelle which provides for a one step process of preparing the polymeric micelle containing a poorly water soluble drug.
• conventional methods employ two steps: 1) a polymeric micelle is formed in an aqueous media and 2) a poorly water soluble drug is incorporated into the micelle in the aqueous polymer solution.
• the present invention also provides a method of incorporating a poorly water soluble drug into a polymeric micelle having a core-shell structure using liquid polyethylene glycol as a phase separation medium, removing the liquid polyethylene glycol and freeze-drying the resulting micellar solution.
• a biocompatible water-miscible organic solvent may be added to the composition of the present invention to facilitate better solubility of the drug.
• the amount of organic solvent added depends on the solubility of the drug, and the preferred content of the solvent is less than 50 wt % based on the amount of poly(ethylene glycol) or its derivatives.
• the present invention further provides an efficient method to effectively incorporate a hydrophobic drug into a polymeric micelle in a polyethylene glycol separating medium.
• Aqueous solutions of micelles from which the polyethylene glycol has been removed can be filtered to sterilize them, freeze-dried and stored as a stable powder formulation.
• the composition can easily be reconstituted as a solution and injected into the body and is therefore is useful for the intravenous administration of poorly water soluble drugs.
• the present invention is directed to a method for preparing a polymeric micelle having a core-shell type structure using liquid polyethylene glycol as a phase separation medium and a method of incorporating a poorly water soluble drug into the polymeric micelle.
• a polymeric micelle composition in a dry-state, is obtained by dialyzing the polymeric micellar PEG solution, containing a drug or not, against water to remove the PEG followed by freeze-drying the resulting solution.
• composition containing an amphiphilic block copolymer having a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component dispersed or suspended in a poly(ethylene glycol) medium are disclosed in copending PCT/KR00/00885, hereby fully incorporated by reference (which has been filed in the U.S. as Ser. No. 09/807,487).
• the amphiphilic block copolymer comprises a hydrophilic poly(alkylene glycol) component and a hydrophobic biodegradable polymer component.
• the polyalkylene glycol suitable as the hydrophilic component in the block copolymer of the present invention is a member selected from the group consisting of polyethylene glycol, monoalkoxy polyethylene glycol, or monoacyloxy polyethylene glycol, wherein the molecular weight of the polyalkylene glycol is preferably within the range of 1,000 ⁇ 20,000 Daltons.
• the hydrophobic biodegradable polymer component of the copolymer of the present invention is a member selected from the group consisting of polylactides, polycaprolactone, copolymers of lactide and glycolide, copolymers of lactide and caprolactone, copolymers of lactide and 1,4-dioxan-2-one, polyorthoesters, polyanhydrides, polyphosphazines, poly(amino acid)s and polycarbonates.
• the hydrophobic biodegradable polymer component of the copolymer of the present invention is a member selected from the group consisting of a polylactide, polycaprolactone, a copolymer of lactide and glycolide, a copolymer of lactide and caprolactone, and a copolymer of lactide and 1,4-dioxan-2-one.
• the molecular weight of the hydrophobic biodegradable polymer component is preferably within the range of 1,000 ⁇ 20,000 Daltons, and more preferably within the range of 1,000 ⁇ 10,000 Daltons.
• the amphiphilic block copolymer of the present invention may be an AB type diblock or an ABA or BAB type triblock copolymer comprising a hydrophilic poly(alkylene glycol) A-block component (A) and a hydrophobic biodegradable polymer B-block component(B), which form micelles in an aqueous medium, and are dissolved or mixed homogeneously in a poly(ethylene glycol) medium.
• amphiphilic block copolymers can be prepared according to methods described in U.S. Pat. Nos. 5,683,723 and 5,702,717, hereby fully incorporated by reference. For example they may be prepared via ring opening bulk polymerization of one of the monomers, such as a lactide, caprolactone, 1,4-dioxan-2-one, or a glycolide, with a polyethylene glycol derivative in the presence of stannous octoate as a catalyst.
• Block copolymers having a poly(amino acid) block are prepared by reaction of an amino acid N-carboxy anhydride with a polyethylene glycol derivative.
• the hydrophilic polyethylene glycol block is preferably in the range of 30 ⁇ 70% by weight of the block copolymer, and most preferably 40 ⁇ 60% by weight.
• the liquid polyethylene glycol used for the phase separation medium in preparing polymeric micelles (containing a poorly water soluble drug) of the present invention is preferably selected from the group consisting of dihydroxy, monoalkoxy, monoacyloxy, dialkoxy, or diacyloxy polyethylene glycol having a molecular weight of 200 ⁇ 20,000 Daltons and a melting temperature of less than 65° C. More preferably, the liquid polyethylene glycol is selected from the group consisting of dihydroxy polyethylene glycol, dialkoxy polyethylene glycol, and diacyloxy polyethylene glycol which are liquid at a temperature of 0 ⁇ 40° C. and has a molecular weight of 200 ⁇ 20,000 Daltons, preferably 200 ⁇ 10,000 Daltons, and most preferably 200 ⁇ 1,000 Daltons. Water, or an aqueous solution, can be added to the liquid polyethylene glycol to facilitate phase separation of the block copolymer micelles. Preferably the amount added will be less than 10% by weight of the liquid polyethylene glycol solution.
• a small amount of an organic solvent can be added to facilitate the solubility of a poorly water soluble drug in the liquid polyethylene glycol that is used for the phase separation medium.
• the solvent should be biocompatible and easily eliminated by evaporation or dialysis.
• ethanol, acetic acid, or acetone can be used as the solvent.
• Ethanol or acetic acid is the preferred selection for this purpose.
• the amount added is preferably 0.1 ⁇ 20% and is most preferably less than 10% by weight of the amount of polyethylene glycol used for the phase separation medium.
• Such amounts of organic solvents are considered, by definition herein, to be insignificant amounts when compared to the amount polyethylene glycol liquid medium.
• hydrophobic drug any drug having a water solubility of less than 10 mg/ml can be used as the “hydrophobic drug” or “poorly water soluble drug” to be incorporated in the polymeric micelle of the present invention.
• hydrophobic drugs include anticancer agents, antiinflammatory agents, antifungal agents, antiemetics, antihypertensive agents, sex hormones, and steroids.
• hydrophobic drugs are: anticancer agents such as paclitaxel, camptothecin, doxorubicin, daunomycin, cisplatin, 5-fluorouracil, mitomycin, methotrexate, and etoposide; antiinflammatory agents such as indomethacin, ibuprofen, ketoprofen, flubiprofen, dichlofenac, piroxicam, tenoxicam, naproxen, aspirin, and acetaminophen; antifungal agents such as itraconazole, and ketoconazole; sex hormones such as testosterone, estrogen, progestone, and estradiol; steroids such as dexamethasone, prednisolone, and triamcinolone; antihypertensive agents such as captopril, ramipril, terazosin, minoxidil, and parazosin; antiemetics such as ondansetron and granisetron; antifungal
• the present invention is particularly useful for administering anti-cancer drugs such as paclitaxel, taxotane, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide, and camptothecin; sex hormones such as testosterone, estrogen, and estradiol; steroids such as triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, and betamethasone; cyclosporine; and prostagladins.
• anti-cancer drugs such as paclitaxel, taxotane, doxorubicin, cisplatin, carboplatin, 5-FU, etoposide, and camptothecin
• sex hormones such as testosterone, estrogen, and estradiol
• steroids such as triamcinolone acetonide, hydrocortisone, dexamethasone, prednisolone, and betamethasone
• cyclosporine and prost
• a polymeric micelle is prepared as follows:
• step (3) Dialyzing the polymeric micellar containing composition formed in step (2), in liquid polyethylene glycol against excess water to remove the liquid polyethylene glycol that was used as a phase separation medium.
• a polymeric micelle containing a hydrophobic drug is prepared by dissolving the drug together with the amphiphilic block copolymer in the liquid polyethylene glycol in step (1) as described above.
• the drug and the amphiphilic block copolymer can be easily dissolved in the liquid polyethylene glycol.
• organic solvent such as ethanol or acetic acid
• a drug containing polymeric micelle composition in the state of a fine powder is obtained by dialyzing the polymeric micellar solution against excess water followed by freeze-drying the resulting solution according to steps (3) and (4).
• the polymeric micellar containing solution can be diluted with distilled water to facilitate dialysis.
• the dialyzed composition containing a poorly water soluble drug obtained in step (3) is filtered through a membrane filter having a pore size of 0.22 ⁇ 0.80 ⁇ m to sterilize the composition and then freeze-dried in an aseptic environment in step (4).
• the block copolymer content of the combined copolymer/polyethylene glycol composition is preferably 1 ⁇ 50% by weight, and more preferably 10 ⁇ 40% by weight.
• the poorly water soluble drug content in the polymeric micelle is preferably 0.1 ⁇ 20% by weight based on the total weight of the drug and the block copolymer, and most preferably 1 ⁇ 15% by weight.
• the stabilizer such as mannitol, sorbitol, lactose, or sucrose, can be added to increase the stability of the freeze-dried micelle of the present invention.
• a stabilizer can be added in an amount of 0.1 ⁇ 200% by weight based on the total weight of the drug and the block copolymer.
• the polymeric micelle prepared according to the present invention has a diameter of 10 ⁇ 500 nm, preferably 10 ⁇ 20 nm, and the micellar composition when dispersed in saline can be used as a carrier for poorly a water soluble drug via various routes: injectable(iv, im, sc); oral; and nasal routes.
• the solution was then poured into cold anhydrous ether ( ⁇ 10 ⁇ 0° C.) to precipitate the polymers, namely, diblock copolymers of monomethoxy polyethylene glycol and polylactide(mPEG-PLA).
• the precipitated polymers were dried at 30° C. under vacuum (0.1 mmHg) for 48 hours.
• a diblock copolymer of monomethoxy polyethylene glycol and poly(lactide-glycolide) was prepared by the same method as in Example 1, using 2 g of monomethoxy polyethylene glycol(molecular weight of 2,000 Daltons), 0.7 g of lactide, and 0.3 g of glycolide in the presence of 0.01 g of stannous octoate as a catalyst.
• a diblock copolymer of monomethoxy polyethylene glycol and poly(lactide-p-dioxanone) (mPEG-PLDO) was prepared by the same method as in Example 1, using 2 g of monomethoxy polyethylene glycol(molecular weight of 2,000 Daltons), 0.5 g of lactide, and 0.5 g of 1,4-dioxan-2-one in the presence of 0.01 g of stannous octoate as a catalyst.
• a diblock copolymer of monomethoxy polyethylene glycol and polycaprolactone was prepared by the same method as in Example 1, using 2 g of monomethoxy polyethylene glycol (molecular weight of 2,000 Daltons), and 0.8 g of caprolactone in the presence of 0.008 g of stannous octoate as a catalyst.
• a diblock copolymer of monomethoxy polyethylene glycol and polylactide was prepared by the same method as in Example 1, using 2 g of monomethoxy polyethylene glycol (molecular weight of 5,000 Daltons), and 1.8 g of lactide in the presence of 0.018 g of stannous octoate as a catalyst.
• the composition obtained from the above step (1) was diluted with 4 ml of distilled water and the aqueous solution was then put into a dialysis bag.
• the liquid polyethylene glycol was removed from the solution by dialyzing the solution against water for 12 hours.
• An aqueous polymeric micellar solution was obtained.
• the dialyzed aqueous micellar solution obtained from the above step (2) was then filtered through a membrane filter, having a pore size of 0.22 ⁇ m, to sterilize it and it was then freeze-dried in an aseptic environment.
• the polymeric micellar composition in powder form was obtained by freeze-drying the aqueous micellar solution.
• Example 6 The polymeric micelles prepared in Example 6 and Comparative Example 1 was dispersed in suitable amount of distilled water to give a concentration of 0.1% (w/v) and the particle size of each micellar solution was determined by a dynamic light scattering (DLS) method.
• the average micelle size of each preparation was nearly the same: 40 nm for Example 6, and 35 nm for Comparative Example 1
• composition obtained from the step (1) above was diluted with 2 ml of distilled water and then put into a dialysis bag.
• the liquid polyethylene glycol was removed from the solution by dialyzing against water for 12 hours, and an aqueous polymeric micellar solution containing paclitaxel was obtained in the dialysis bag.
• the dialyzed aqueous solution obtained from the step (2) above was filtered through a membrane filter, with a pore size of 0.22 ⁇ m, to sterilize it, and then freeze-dried in an aseptic environment.
• a polymeric micellar composition containing paclitaxel was prepared by a method described in U.S. Pat. No. 5,510,103, hereby incorporated by reference.
• Step 1 Formation of a Polymeric Micelle
• Step 2 Incorporation of a Drug
• the aqueous solution obtained from Step 2 above was filtered through a membrane filter with a pore size of 0.22 ⁇ m, to sterilize it, and was then freeze-dried in an aseptic environment giving a powder state of the polymeric micellar composition.
• Example 7 The polymeric micelles prepared in Example 7 and Comparative Example 2 were dispersed in a suitable amount of distilled water to give a concentration of 0.1% (w/v) and the particle size of each micellar solution was determined by a dynamic light scattering (DLS) method.
• the average micelle size of each preparation was nearly the same: 55 nm for Example 7, and 50 nm for Comparative Example 2.
• Example 7 The amount of drug incorporated in each composition prepared in Example 7 and Comparative Example 2 was also determined by a HPLC assay.
• the polymeric micellar composition of the present invention exhibited a higher loading efficiency than that prepared according to U.S. Pat. No. 5,510,103.
• composition obtained from the step (1) above was diluted with 4 ml of distilled water and then put into a dialysis bag.
• the liquid polyethylene glycol was removed from the solution by dialyzing against water for 12 hours, and an aqueous polymeric micellar solution containing cyclosporine A was obtained.
• the dialyzed aqueous solution obtained from the step (2) above was filtered through a membrane filter, with a pore size of 0.22 ⁇ m, to sterilize it, and then freeze-dried in an aseptic environment.
• a polymeric micellar composition containing paclitaxel was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.85 g paclitaxel: 0.15 g diethoxy polyethylene glycol (mw: 600 Daltons): 5.00 g
• a polymeric micellar composition containing paclitaxel was prepared by the method described in Example 8 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.85 g paclitaxel: 0.15 g dimethoxy polyethylene glycol (mw: 600 Daltons): 4.00 g ethanol: 1.00 g
• a polymeric micellar composition containing paclitaxel was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.98 g paclitaxel: 0.02 g dimethoxy polyethylene glycol (mw: 300 Daltons): 4.00 g
• a polymeric micellar composition containing paclitaxel was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.95 g paclitaxel: 0.05 g diacetyloxy polyethylene glycol (mw: 300 Daltons): 4.00 g
• a polymeric micellar composition containing paclitaxel was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.80 g paclitaxel: 0.10 g polyethylene glycol (mw: 200 Daltons): 5.00 g
• a polymeric micellar composition containing cyclosporine A was prepared by the method described in Example 8 using the following ingredients:
• mPEG-PLA (mw: 2,000-1,800 Daltons): 0.90 g cyclosporine A: 0.10 g dimethoxy polyethylene glycol (mw: 200 Daltons): 3.60 g acetic acid: 0.40 g
• a polymeric micellar composition containing testosterone was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLDO (mw: 2,000-1,800 Daltons): 0.95 g testosterone: 0.05 g polyethylene glycol (mw: 600 Daltons): 2.00 g
• a polymeric micellar composition containing doxorubicin was prepared by the method described in Example 7 using the following ingredients:
• mPEG-PLDO (mw: 2,000-1,800 Daltons): 0.90 g doxorubicin: 0.10 g polyethylene glycol (mw: 600 Daltons): 2.00 g
• a polymeric micellar composition containing a prostaglandin was prepared by the method described in Example 8 using the following ingredients:
• mPEG-PCL (mw: 2,000-1,800 Daltons): 0.95 g prostaglandin: 0.05 g polyethylene glycol (mw: 600 Daltons): 3.50 g ethanol: 0.50 g

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